Abstract
Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) functions as an oncogene in colorectal cancer (CRC), promotes the progression of CRC, and is associated with poor prognosis in patients. Studies have found that NUCKS1 promotes tumor cell metastasis, yet its role in CRC invasion and metastasis remains unclear. To investigate this, transwell migration and invasion assay, wound healing assay, and immunofluorescence assay were performed in vitro. Additionally, label-free protein quantification, coimmunoprecipitation (Co-IP), q-PCR, and Western blotting were utilized to analyze NUCKS1's molecular mechanisms in CRC. In vivo, CRC cells were injected into the tail vein to examine NUCKS1's impact on lung and liver metastasis in mice, with hematoxylin-eosin (HE) staining used to evaluate metastatic lesion sizes. Results indicated higher NUCKS1 expression in metastatic CRC compared to non-metastatic samples. Knockdown of NUCKS1 in vitro inhibited CRC invasion and metastasis. Moreover, NUCKS1 was initially found to upregulate HDAC2 expression by inhibiting the lysosomal pathway, activating AKT, and thus promoting CRC invasion and metastasis. In vivo, overexpression of NUCKS1-induced lung and liver metastasis was suppressed by HDAC2 knockdown or intraperitoneal administration of the HDAC2 inhibitor Santacruzamate A. These findings suggest that NUCKS1 contributes to CRC invasion and metastasis by stabilizing HDAC2 and activating AKT, highlighting NUCKS1 and HDAC2 as potential therapeutic targets for CRC.